Cutaneous head and neck melanoma: the old and the new.
ABSTRACT The incidence rate of malignant melanoma has shown a rapid worldwide rise in recent years. The staging and management of head and neck melanoma presents some unique challenges. Surgery remains the cornerstone of treatment, while sentinel node biopsy is the most accurate staging modality for regional disease. The complex regional anatomy and lymphovascular drainage of this region may account for the increased biologic aggressiveness and treatment challenges of this disease. Improved understanding of the radiobiology of melanoma has resulted in new adjuvant radiotherapy approaches, yielding improved control rates. The treatment outcomes of metastatic head and neck melanoma remain disappointing but important progress has been made in the understanding of melanoma biology.
- SourceAvailable from: Maria Karasarides[show abstract] [hide abstract]
ABSTRACT: The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in approximately 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-alpha. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-kappaB (NF-kappaB) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.Cancer Research 02/2007; 67(1):122-9. · 8.65 Impact Factor
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ABSTRACT: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.Journal of Clinical Oncology 04/1999; 17(3):976-83. · 18.04 Impact Factor
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ABSTRACT: In a recent clinical trial involving patients with metastatic melanoma, immunosuppressive conditioning with fludarabine and cyclophosphamide resulted in a 50% response rate in robust long-term persistence of adoptively transferred T cells. Experimental findings indicate that lymphodepletion prior to adoptive transfer of tumor-specific T lymphocytes plays a key role in enhancing treatment efficacy by eliminating regulatory T cells and competing elements of the immune system ('cytokine sinks'). Newly emerging animal data suggest that more profound lymphoablative conditioning with autologous hematopoetic stem-cell rescue might further enhance treatment results. Here we review recent advances in adoptive immunotherapy of solid tumors and discuss the rationale for lymphodepleting conditioning. We also address safety issues associated with translating experimental animal results of total lymphoid ablation into clinical practice.Nature Clinical Practice Oncology 01/2007; 3(12):668-81. · 8.00 Impact Factor